A Literature Review on the Status and Effects of Salvia Divinorum on

Transcription

A Literature Review on the Status and Effects
of Salvia Divinorum on Cognitive, Affective,
and Behavioral Functioning
Parker L. Mott
DISSERTATION.COM
Boca Raton
A Literature Review on the Status and Effects of Salvia Divinorum on
Cognitive, Affective, and Behavioral Functioning
Copyright © 2011 Parker L. Mott
All rights reserved. No part of this book may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopying, recording, or by any information
storage and retrieval system, without written permission from the publisher.
Dissertation.com
Boca Raton, Florida
USA • 2011
ISBN-10: 1-61233-777-5
ISBN-13: 978-1-61233-777-7
EFFECTS OF SALVIA DIVINORUM 2
TABLE OF CONTENTS
ABSTRACT.....................................................................................................................................5
CHAPTER
1. HISTORY AND BACKGROUND.......................................................................................6
Introduction..........................................................................................................................6
Background..........................................................................................................................7
Psychoactive Effects............................................................................................................8
Traditional Uses...................................................................................................................9
Pharmacology/Chemistry...................................................................................................10
Current Status....................................................................................................................12
Prevalence..........................................................................................................................13
Subjective Experience........................................................................................................15
Purpose of the Present Review..........................................................................................16
2. REVIEW OF EMPIRICAL LITURATURE ON SALVIA DIVINORUM.........................19
Cognitive Functioning: Introduction to the Cognitive Process.........................................19
Cognitive/Subjective Effects of Salvia Divinorum................................................19
Salvinorin-A and Activation of κ-opioid receptors in Cognition..........................20
Salvinorin-A, κ-opioid receptors, and Brain Locations.........................................21
Affective Functioning: Introduction to the Affective Process..........................................22
Reported Affective Responses to Salvia Divinorum.............................................23
Salvinorin-A and Depression.................................................................................23
Behavioral Functioning: Introduction...............................................................................26
Physiological Responses........................................................................................26
Gastrointestinal Effects.........................................................................................26
Sedation and Reduction in Locomotion.................................................................27
Pain/Antinociceptive/Analgesic Effects................................................................27
Addiction Potential and Rewarding Properties......................................................27
Salvinorin-A and Cocaine......................................................................................28
3. DISCUSSION.......................................................................................................................30
Cognitive Functioning.......................................................................................................30
Learning, Memory, and Implications on Academic Functioning..........................30
Implications of Salvia Divinorum in Localized Areas of the Brain......................31
The Effects of Salvia Divinorum on Cognitive Functioning.................................34
DSM-IV-TR and Cognitive Effects from Salvia Divinorum Use.........................35
Affective Functioning........................................................................................................37
The Effects of Salvia Divinorum use on Anxiety..................................................37
Salvia Divinorum and Depression.........................................................................38
The Effects of Salvia Divinorum and Affective Functioning................................44
DSM-IV-TR and Affective Effects of Salvia Divinorum Use...............................45
Behavioral Functioning......................................................................................................47
Physiological Response to Salvia Divinorum use.................................................47
Salvia Divinorum as an Analgesic.........................................................................47
Salvia Divinorum and Abuse/Addiction Potential................................................48
Salvia Divinorum Potential for Abuse and the DSM-IV-TR................................49
Co-occurring Substance Use and Salvia Divinorum.............................................52
The Effects of Salvia Divinorum use on Behavioral Functioning.........................52
Summary............................................................................................................................53
4. RECOMMENDATIONS......................................................................................................55
Recommendations for Study Regarding Cognitive Functioning.......................................55
Recommendations for Further Study on Salvia Divinorum and
Memory Functioning.............................................................................................55
Areas for Further Research to After-Effects of Salvia Divinorum........................56
Areas for Further Study on Salvia Divinorum and Brain Activity........................56
Recommendations for Study Regarding Affective Functioning........................................57
Anti-Anxiety Effects and Areas for Further Study................................................57
Recommendations for Further Research on Depression
and Salvia Divinorum............................................................................................58
Recommendations for Structured Interview Development and
Data Collection......................................................................................................59
Recommendations for Study Regarding Behavioral Functioning.....................................60
Physiological Effects versus Psychoactive Experience.........................................60
Recommendations for Further Study on Salvia Divinorum and
Abuse Potential......................................................................................................60
Recommendations for Research on Motor Functioning and
Salvia Divinorum...................................................................................................62
Issues for Future Study and Clinical Attention..................................................................62
Areas for Clinicians to be Aware...........................................................................62
Note of Caution for Clinicians and Recreational Users.........................................63
Closing Thoughts...............................................................................................................64
REFERENCES..............................................................................................................................65
Abstract
Salvia divinorum is a hallucinogenic herb that was originally used in the Mazatec Indian
culture of Oaxaca, Mexico for spiritual and medicinal purposes (Wasson, 1962). Salvia
divinorum produces powerful hallucinogenic effects when the leaves are chewed, orally
consumed in a liquid state, or dried and smoked. It’s active ingredient is Salvinorin-A (Roth et
al., 2002; Siebert, 1994), a highly selective kappa (κ)-opioid receptor agonist (Roth et al., 2002),
that researchers consider to be the most potent naturally occurring hallucinogen (Ortega, Blount
& Manchand, 1982; Siebert, 1994; Valdes et al., 1984). In recent years, the use of Salvia
divinorum as a recreational drug has become increasingly popular (Vortherms & Roth, 2006),
facilitated by the availability of the drug and videos (e.g., YouTube) documenting its
hallucinogenic effects on the internet (Gonzalez, Riba, Bouso, Gomez-Jarabo, & Barbanoj,
2006). The purpose of the current clinical research project is to critically review the literature to
investigate the effects Salvia divinorum use has on cognitive, affective, and behavioral
functioning in humans. The review has implications for research on depression, anxiety,
addiction, Parkinson’s disease, and Alzheimer’s disease. The study also provides a review of
DSM-IV-TR diagnoses and precautions in diagnosing for clinicians. Based on this review,
recommendations are provided in areas for future research, development of assessment
instruments, and areas requiring clinical attention. Furthermore, the current study will act as a
comprehensive review of the history, background, and research of Salvia divinorum for the use
in future studies and for the purpose of educating clinicians and the general public about the
substance.
Chapter 1
History and Background
Introduction
Salvia divinorum is one of more than 700 members of the plant genus “salvia,” and is
considered a member of the sage and mint family (Valdes & Seymour, 1998). Salvia divinorum
was primarily used by the Mazatec Indian culture of Oaxaca, Mexico for medicinal and spiritual
purposes (Wasson, 1962). Medicinal uses include treatment of diarrhea and headaches (Valdes,
Diaz, & Paul, 1983). However, the plant also possesses psychoactive properties that induce
powerful hallucinations that are useful in spiritual and religious rituals (Wasson, 1962). Salvia
divinorum is generally used by (a) chewing the leaves, (b) drinking juice made from crushing the
leaves, or (c) smoking dried leaves or extracts (Siebert, 1994). In recent years, Salvia divinorum
has become an increasingly popular recreational drug (Vortherms & Roth, 2006), facilitated by
its availability on the internet, as well as information on how to use it and videos (e.g., YouTube)
documenting its hallucinogenic effects (Gonzalez, Riba, Bouso, Gomez-Jarabo, & Barbanoj,
2006). Salvia divinorum tends to be attractive to adolescents because it is often marketed as an
alternative to marijuana and advertised as being highly safe. It is also easy to obtain and legal in
most states. However, despite an increase in Salvia divinorum research over the last 20 years,
little is known about the short- and long-term effects on an individual’s cognitive, affective, and
behavioral functioning. Some studies have found Salvia divinorum to have therapeutic
properties, but other studies have failed to replicate these findings. In the first chapter, the author
will provide an in-depth description of the definition of Salvia divinorum. The focus will be to
inform the reader about the herb’s history, pharmacology, status in the world, and prevalence.
Background
Salvia divinorum is an herb in the Labiatae, or mint family, and is native to certain areas
in the Sierra Mazateca of Mexico (Epling & Játiva-M, 1962). The plant grows to well over one
meter in height and consists of large green leaves, hollow square stems, and has white flowers
with purple calyces (Valdes, Díaz & Paul, 1983). The sage is found in forest ravines and other
moist or humid areas of the Sierra Mazateca.
There are a number of common names for Salvia divinorum and many are related to the
herb’s association with the Virgin Mary (Valdes, Díaz & Paul, 1983; Wasson, 1962). The
Mazatecs refer to Salvia divinorum as hojas de la Pastora, or hojas de María Pastora ("leaves of
the Shepherdess" or "leaves of Mary the Shepherdess"), and may also be known as “ska pastora”
or “ska Maria pastoria.” The Mazatecs believe Salvia divinorum is the incarnation of the Virgin
Mary, and a great deal of care is taken not to damage the plant when picking the leaves. Other
common street names include “Diviners Sage,” “Mystic Sage,” and “Magic Mint” (Babu,
McCurdy & Boyer, 2008).
R. Gordon Wasson was the first to publicize Salvia divinorum, in 1953, based on his
work studying the role of mushrooms in the religious life of the Mazatecs. The Mazatecs used
several hallucinogenic plants in their religious rituals (i.e., Salvia divinorum, psilocybin
mushrooms, peyote, and morning glory seeds containing lysergic acid amide). The Mazatecs
used Salvia divinorum when mushrooms were scarce. Wasson carefully documented how the
plant was prepared and used in religious rituals. He also records his own experience with the
drug:
“The effect of the leaves came sooner than would have been the case with the
mushrooms, was less sweeping, and lasted a shorter time. There was not the slightest
doubt about the effect, but it did not go beyond the initial effect of the mushrooms-
dancing colors in elaborate, three-dimensional designs. Whether a larger dose would have
produced a greater effect, I do not know” (Wasson, 1962).
In 1962, Wasson gave the first specimens of the plant to Carl Epling at the University of
California (Siebert, 1994; Wasson, 1962), at which point it was formally named and classified.
Psychoactive Effects
As mentioned, Salvia divinorum produces powerful hallucinogenic effects when the
leaves are chewed, orally consumed, or dried and smoked. When smoked, the hallucinogenic
effects occur quite rapidly and often within seconds of inhalation. The onset of the effects after
chewing fresh leaves takes longer due to the slower rate of absorption, but still may be felt as
early as five minutes after ingestion. Despite the powerful nature of Salvia divinorum, the
hallucinatory effects are short-lasting and often peak and reside within three to ten minutes after
smoking the leaves.
The psychoactive effects are largely subjective which make them difficult to study. The
effects are said to be highly dose-dependent with larger doses causing extreme hallucinatory
experiences (Lange, Reed, Ketchie-Croff, & Clapp, 2008). Siebert (1994) concluded the
psychoactive effects experienced by Salvia divinorum users depends on factors such as dosage,
set, and setting. He found that people frequently report visual hallucinations; and with higher
dosages may experience out of body sensations. In addition, reports of depersonalization,
transforming into objects, traveling into the past or other dimensions, flying through space, and
laughter have all been commonly reported by those who have used the substance. Furthermore,
“bad trips” have been reported by those who experienced hallucinations, and it is speculated
these experiences may be related to the dosage as well as environmental influences.
Traditional Uses
As previously mentioned, Salvia divinorum was used by shamans for medicinal,
ritualistic, and divination purposes. The plant species known as “salvia” is used for medicinal
purposes in cultures throughout the world, and the name itself comes from the Latin word
“salvare,” which means “to save.” Unlike Western cultures, Mazatec medicine and religion are
united in the treatment of illnesses. Mazatecs are nominally Catholic Christians who
incorporated many features of their traditional beliefs into conceptions of God, the Virgin Mary,
and Saints, whom they view as being healers (Valdes, Díaz & Paul, 1983).
Shamans used Salvia divinorum to induce hallucinations for several spiritual and
medicinal purposes. One such purpose would be when an individual suffers from an unknown
illness and the herb is used to aid in diagnosis (Kapit, 2003). The shaman will gather the leaves
while praying and then create an infusion with the fresh leaves of the plant. At midnight the
curandero, or “shaman healer,” along with the patient and a witness will go to a dark place where
the patient will ingest the solution. The patient will then enter into a semi-delirious trance and the
curandero will make a diagnosis based on the patient’s speech. The session will end by bathing
the patient in a portion of the infusion and the next morning the patient will have been cured of
the illness (Kapit, 2003; Valdes, Díaz & Paul, 1983; Weitlaner, 1952).
Salvia divinorum is also used for shamanic training or apprenticeship into becoming a
healer. Psychotropic plants are closely associated with the training, which can last several years.
The Mazatecs believe the herb allows them to become acquainted with the “way to heaven,”
where they are taught by visions, and may speak with the Virgin Mary, God, and Saints. Through
the visions, and under the supervision of the master who also consumes the plant with the
apprentice, the apprentice learns the ways of healing and the knowledge of medicinal plants by
visiting a tree in Heaven that possesses all of the herbs. Salvia divinorum is also used to foretell
the future and obtain answers to questions about friends, family, or enemies (Valdes, Díaz &
Paul, 1983).
Salvia divinorum has also been used by curanderos to help find lost objects or animals,
along with helping victims of crimes identify their perpetrator. The shaman will administer a
dose of prepared Salvia divinorum to the person and then listens carefully as they speak. It is
believed the person will tell the shaman the location of the lost object or discuss the crime
committed (Kapit, 2003).
According to Valdes and colleagues (1983), Salvia divinorum is not just used for the
psychoactive or hallucinatory effects in the Mazatec culture. It is also a common practice for
healers to administer small doses of Salvia divinorum to treat various ailments, such as providing
relief from headaches, rheumatism, and diarrhea. It is believed that Salvia divinorum can help
alleviate pain related to headaches and rheumatism; however, according to cuarenderos high
doses that induce visions may leave one with a headache the following day. Shamans also
believe that small doses of the herb can help one to defecate or eliminate diarrhea. Furthermore,
there is a “semi-magical” disease known as panzon de barrego, or swollen belly, which is caused
by an evil sorcerer. The disease consists of the victim’s swollen midsection which is due to a
“stone” put inside of the individual by the sorcerer. Salvia divinorum is thought to eliminate the
“stone” and will result in the stomach shrinking down to normal size (Valdes, Díaz & Paul,
1983).
Pharmacology/Chemistry
Salvia divinorum owes its psychoactive properties to salvinorin-A, which is the main
active principle of the herb (Roth et al., 2002; Siebert, 1994). Salvinorin-A is a non-nitrogenous
neoclerodane diterpene and is thought to be the most potent naturally occurring hallucinogen
(Ortega, Blount & Manchand, 1982; Siebert, 1994; Valdes et al., 1984). Salvinorin-A is a potent
and highly selective kappa (κ)-opioid receptor agonist and is considered the first nonalkaloid
opioid subtype-selective substance (Roth et al., 2002). Furthermore, salvinorin-A does not show
affinity to the µ- or δ-opioid receptors (Wang et al., 2005). Salvia divinorum’s unique chemical
structure and qualities are unlike that of other classic hallucinogens and substances of abuse such
as psilocybin, mescaline, lysergic acid diethylamide (LSD), and ketamine (Roth et al., 2002;
Siebert, 1994; Valdes & Seymour, 1998). In contrast with these psychedelic substances,
salvinorin-A does not interact with the serotonin-2A receptor (5HT2), but presumably induces its
psychotropic effects through the activation of the κ-opioid receptors. Thus, Salvia divinorum is
considered to be in a class of hallucinogen of its own (Gonzalez et al., 2006; Roth et al., 2002).
Although salvinorin-A is the main active principle in Salvia divinorum, other ingredients
of salvinorin have also been identified. Salvinorin B-F has been identified in research, and
although the function of these other ingredients is not well understood, they are thought to be
rather benign or inactive. However, it has been suggested that salvinorin B may be a metabolite
of salvinorin-A (Schmidt et al., 2005).
Because salvinorin-A is not water-soluble, it is mainly absorbed through the respiratory
system and, to a lesser extent, by the oral mucosa (Bucheler, Gleiter, Schwoerer, & Gaerner,
2005). PET scan studies of baboons indicate salvinorin-A rapidly crosses the blood brain barrier
(BBB), reaches 3.3% of the injected dose within 40 seconds, and will clear to half of peak by
eight minutes (Hooker et al., 2008). Thus, the study reveals the extraordinarily rapid uptake and
short duration of salvinorin-A activity in the body.
According to a study by Mowry, Mosher, and Briner (2003), salvinorin-A displays
minimal physiologic effects. It was observed that body temperature, sympathetic nervous system
activity, and cardiac effects are minimal with Salvia divinorum use. Moreover, there were no
reports of cardiovascular events nor were there any symptoms that would suggest autonomic
nervous system effects. Mowry et al. also investigated the toxicity of Salvia divinorum and the
effects of repeated injections of salvinorin-A over time. The researchers injected mice with
dosages well in excess of human consumption and found no histological changes. Thus, Mowry
et al. found that long-term administration in mice seemed to confirm that salvinorin-A is a fairly
benign substance with low toxicity. These findings should be interpreted cautiously, however,
given that the study was limited in time and conducted on non-human subjects that demonstrate
minimal psychological activity.
Current Status
The popularity of Salvia divinorum appears to have risen over the last ten years through
its availability on the internet and its notoriety based on news reports. The internet, along with
“smoke shops” or “head shops,” market Salvia divinorum as a legal alternative to marijuana,
which appeals to marijuana users as well as adolescents who can legally buy the product under
the age of 18 in many states and countries. Although the effects are dissimilar to that of
marijuana, Salvia divinorum attracts a new following of individuals who want to experiment
with a “safe” hallucinogen without engaging in illegal activity (Vince, 2006) or without
experiencing longer-lasting psychoactive effects associated with other hallucinogens. However, a
study by Wolowich, Perkins, and Cienki (2006) tested five samples of Salvia divinorum
purchased from various retailers to test the purity of the substance. The researchers found
variability within the samples and inconsistency in the labeling of the product prevented a
reliable determination of the amount of salvinorin-A concentration and extract consumed.
Samples tested included other substances not advertized, which suggests one cannot be sure that
the product purchased is safe.
Salvia divinorum is currently legal in most states, but is banned in Delaware, Florida,
Illinois, Louisiana, Maine, Missouri, North Dakota, Oklahoma, Kansas, Tennessee, and Virginia.
Many states currently have legislation pending on restricting or banning Salvia divinorum. Most
states that banned Salvia divinorum have done so only in the last few years. Salvia divinorum is
also illegal in Australia, Finland, Denmark, Spain, and Norway, Belgium, Estonia, Italy, and
Sweden (McDonough, et al., 2008; Singh, 2007).
Prevalence
According to a face-to-face interview survey by The National Survey on Drug Use and
Health (NSDUH) about 1.8 million people age 12 or older have used Salvia divinorum in their
lifetime, and approximately 750,000 did so in the year 2006. In addition, young adults ages 18 to
25 were nearly three times more likely than youths aged 12 to 17 to have used Salvia divinorum.
The study also found that males were 3 to 4 times more likely to have used Salvia divinorun than
females (Substance Abuse & Mental Health Services Administration Office of Applied Studies,
2008).
The first study of Salvia divinorum use in college students was conducted by Lange,
Reed, Ketchie-Croff, and Clapp (2008), with data obtained in 2006 through 2007. They
concluded that Salvia divinorum use in college students (4.4%) was comparable to that of other
illicit drugs such as ecstasy (5%) and cocaine (7.1%). However, there are a number of
shortcomings in the study. First, it consisted of students from a single university that completed
internet based self-report measures. Moreover, the results could have been further hindered based
on the state legal restrictions on Salvia divinorum and could show differing rates due to the
legality and availability of the substance (Lange et al., 2008)
In another study of college students, Khey, Miller, and Griffin (2008) found that an
overwhelming majority 81.9% reported learning about the drug through their friends, and 4.8%
learned about the substance from a class, while only 2.7% of student learned about Salvia
divinorum via the Internet. Thus, Salvia divinorum is not primarily an internet phenomenon, as
previously thought. Indeed, internet sales accounted for only 9.1% of the total Salvia divinorum
sales, and that the vast majority (77%) of Salvia divinorum was purchased from stores or “head
shops.” In addition, the study suggests that Salvia divinorum use occurs more often in groups
than used on an individual basis, lending it to be more of a social activity. Khey et al. concluded
that although Salvia divinorum use does exist within a college population, use occurs most often
in white male students from wealthy backgrounds, along with those who use marijuana on a
regular basis. Based on the findings of this survey, it may be hypothesized that the media
attention given to Salvia divinorum may increase interest in the substance along with possibly
increasing its use and prevalence (Khey et al., 2008). However, the study consists of several
limitations which may have an impact on the findings. First, the study was conducted at a single
university which may consist of a particular demographic such as, culture, SES, gender, or race.
Secondly, in terms of purchasing the substance from a store versus the internet, it is possible the
results were swayed based on availability. For example, it is possible a “head shop” was within
walking distance of the university which suggests students are more likely to have purchased the
product from a store. Another limitation in the study is the use of self-report measures in a
college setting. It is possible the sample was gathered using collusion or secondary gain, such as
extra credit provided for participating in the study versus participating voluntarily.
Subjective Experience
Siebert (1994) concluded the effects experienced by Salvia divinorum users depends on
factors such as dosage and setting. He found that people frequently report seeing visions of
people, objects, or places; and with dosages exceeding 1mg may experience out of body
sensations. While in the midst of the psychoactive effects, he reported that people will get up and
move around with no apparent awareness of their movements or behavior, may speak gibberish,
or laugh hysterically. Siebert goes on to list several common themes with examples of visions or
sensations experienced by Salvia divinorum users which include: (a) becoming objects, (b)
visions of two dimensional surfaces, films, or membranes; (c) revisiting places in the past such
as childhood; (d) loss of body or identity; (e) sensations of motion; (f) uncontrollable laughter; or
(g) overlapping realities.
Gonzalez and colleagues (2006) obtained systematic information on the pattern of use
and the nature of the subjective effects elicited by Salvia divinorum in recreational users. Selfreport questionnaires that included the Hallucinogen Rating Scale (HRS), the State Trait Anxiety
Inventory-S (STAI-S), and the Altered States of Consciousness Questionnaire were administered
to 18 male and 14 female participants with a mean age of 25 to obtain demographical and
subjective effect information of Salvia divinorum use. Results of the study found that 88% first
used the substance within the last year, with an average use of two times. Moreover, all
participants reported having smoked the substance in extract-form over chewing the leaves.
Regarding their experience while using the drug, 75% described the experience as
“intense” “very intense” or “extremely intense.” The reported positive effects included the “trip”
(41%), euphoria (28%), and the dissociation (19%) elicited by the substance. Negative effects
endorsed by participants included the short duration of effects (38%) and lack of control over the
experience (16%). Forty-four percent of participants reported some degree of malaise, hang-over,
mental fatigue, or comedown immediately after the acute effects of use. Forty-four percent of
participants reported that they would like to use Salvia divinorum regularly. Most participants
(63%) reported that the effects of Salvia divinorum were most similar to those of psilocybin
mushrooms (55%). Of note, only 20% of participants reported the effects to be similar to that of
marijuana, which is interesting given that Salvia divinorum has been traditionally marketed as an
alternative to marijuana (Gonzalez et al., 2006).
The study had several substantial limitations. First, the sample size was small. Second,
self-report subjects may exhibit a tendency to over- or under-report substance use. Third, many
participants reported regularly using other drugs, and thus some of the effects may have been due
to other substances. Lastly, researchers were unable to control dosage of the drug.
In a web-based study of 500 users, it was found that after-effects of using Salvia
divinorum included feelings of increased insight (47%), improved mood (44.8%), calmness
(42.2%), and an increased sense of connection with the universe or nature (39.8%). In addition,
25.8% of participants reported persisting positive effects felt 24 hours after use which usually
include an increased sense of well-being (Baggott, Erowid, Erowid, & Mendelson, 2004).
Purpose of the Present Review
Although Salvia divinorum has been used for a number of years in the Mazatec culture
for medicinal and spiritual purposes, use in the United States for recreation has been fairly
recent. Despite advancements in salvinorin-A research, little is known about Salvia divinorum
and its effects on the body. The vast majority of research on Salvia divinorum appears to be
related to the plant’s pharmacology and chemical composition, while few studies have examined
the short-term and long-term effects or potential impact on psychological functioning. Some
researchers suspect that the drug may provide a number of benefits in the future, based on the
active component and its action on κ-opioid receptors. For example, researchers have suggested
that the study of Salvia divinorum may advance knowledge and treatment of schizophrenia,
depression, bipolar disorder, and certain types of dementias like Alzheimer’s, Huntington’s, and
Pick’s diseases may be derived from research with salvinorin-A. Furthermore, drug abuse of
certain substances such as cocaine may be better understood and medically treated with
medication designed to work on the κ-opioid receptors in the brain. Moreover, activation of the
κ-opioid receptors induces a number of behavioral effects such as analgesia and sedation (Roth et
al., 2002), which suggests its potential use as a pain reducer.
Despite the potential benefits of studying Salvia divinorum, many questions related to the
substance remain unanswered. Unfortunately, there are political, legislative, and social decisions
to consider based on the limited or lack of research on Salvia divinorum. In addition, public
image of Salvia divinorum tends to be negative in large part due to internet posted videos on
YouTube which portray the herb in a disturbing manner. Adolescents and young adults post
public videos that show irresponsible and immature behavior. These videos show users in a
trance-like state or appearing to have seizure-like symptoms and often end with the users
experiencing a “bad trip.” These legislative decisions and laws restricting or banning Salvia
divinorum often limit or eliminate the ability to research and study the active principle in Salvia
divinorum, thus losing potential benefits the substance may offer to medicine. Therefore, the
purpose of the current review is to critically evaluate the literature and research available related
to the potential effects Salvia divinorum has on cognitive, affective, and behavioral functioning
in humans. Based on this review, the author will provide recommendations in areas for
improvement and future research. Furthermore, the review will act as a comprehensive review of
the history, background, and research of Salvia divinorum for use in future studies and for the
purpose of educating clinicians and the general public about Salvia divinorum.
Chapter 2
Review of Empirical Literature on Salvia Divinorum
Cognitive Functioning: Introduction to the Cognitive Process
The author will begin the present review by focusing on research pertaining to how
Salvia divinorum impacts cognitive functioning. For the purpose of this critical literature review,
cognitive functioning will be defined as the process and activity which takes place in the regions
of the brain during Salvia divinorum use. It will include areas in the brain where studies have
shown that salvinorin-A is active during use. The author will review research that identifies
cognitive activity associated with Salvia divinorum use, along with studies related to human
perception and how it may impact an individual’s emotions and behavior. As such, cognitive
functioning is considered interrelated with affective and behavioral processes. For example, the
discussion may focus on how hallucinations impact an individual’s thought process, but may also
impact behaviors and emotional state as well.
Cognitive/subjective effects of Salvia divinorum. A prominent feature of Salvia
divinorum use is the psychoactive and hallucinogenic effects. Cognitive and subjective effects
that have been reported in studies include but are not limited to feelings of euphoria,
dissociation, increased insight, unusual thoughts, depersonalization, disconnection from reality,
hallucinations or colored visions, and loss of consciousness (Baggott et al., 2004; Bucheler et al.,
2005; Gonzalez et al., 2006; Siebert, 1994).
In a case study, Bucheler et al. (2005) interviewed a 19-year-old high school student who
reportedly had been chewing and smoking Salvia divinorum approximately twice a week for
approximately six months. The student reported depersonalization and widening of
consciousness, as well as difficulty learning or memorizing school assignments. The individual
did not attribute the memory difficulties to the drug itself, rather considered it a result of needing
to reflect on his perceptual experience. The single case study not only demonstrates the
psychoactive effects of Salvia divinorum, but also the impact on cognitive functioning after
using the substance.
Salvinorin-A and activation of κ-opioid receptors in cognition. As previously
mentioned, salvinorin-A is a potent and highly selective κ-opioid agonist that has little
resemblance to classical hallucinogens (Roth et al, 2002). Human studies with selective κ-opioid
agonists have shown that activation of the receptors induce visual distortions and
depersonalization (Walsh, Strain, Abreu, & Bigelow, 2001). Therefore, the κ-opioid receptor
system plays a prominent role in the modulation and regulation of human perception and
cognition (Roth et al., 2002). Taken together, this suggests that Salvia divinorum, or more
specifically salvinorin-A, has a profound effect on perception and logical thinking.
Salvinorin-A, κ-opioid receptors, and brain locations. Hooker et al. (2008) used
Positron Emission Tomography (PET) to measure the pharmacokinetics and distribution of
salvinorin-A within the brain and peripheral organs of six female baboons. They found that
salvinorin-A quickly entered the brain and attained maximum concentration within 40 seconds.
In addition, it was observed to clear the brain rapidly with a half-life peak of 8 minutes.
Furthermore, salvinorin-A was widely distributed throughout the brain in both the cortical and
subcortical regions. They found the highest concentration of salvinorin-A in the cerebellum and
visual cortex, which may account for Salvia divinorum’s hallucinogenic effects. Hooker et al.
(2008) estimated that less than 10 mg of salvinorin-A in the human brain could account for the
psychoactive properties of Salvia divinorums.
Hooker, Patel, Kothari, and Schiffer (2009) investigated downstream effects of
salvinorin-A such as changes secondary to neuron activation. The goal of their study was to
identify brain regions and neural circuits associated with salvinorin-A mediated effects. They
used a PET scan to examine regional changes in 19 rat brains. Using this technique, their
research provided the first map of cerebral metabolic activation along with behaviors in rodents.
Their findings demonstrated increased metabolic activity in the periaqueductal gray, bed nucleus
of the stria terminalis, and cerebellar vermis. Furthermore, neural activity was not limited to
regions associated with a high density of κ-opioid receptors. Significant bilateral activations
were also observed in areas of the brain which had little to no κ-opioid receptors, such as the
hypothalamus and auditory, sensory, and frontal cortices. Moreover, increased activity was also
seen in the left ventral pallidum which is located within the basal ganglia, and right lateral
geniculate nucleus which is part of the thalamus. Furthermore, decreases in metabolic activity
were observed in the caudate putamen, superior colliculus, hippocampus, and medial brainstem.
These findings by Hooker et al. indicate that the response to salvinorin-A in the brain goes well
beyond the immediate κ-opioid receptor effects, and involves a larger and more complex
network of neural connections and activity which respond to the initial κ-opioid receptor effects.
For instance, activation of the κ-opioid receptors can cause an increase or decrease in
metabolism that result in additional activation or inhibition of neural systems in various regions
of the brain.
Zhang, Butelman, Schlussman, Ho, and Kreek (2005) observed the effects of salvinorinA on dopamine levels in the caudate putamen and nucleus accumbens. They also attempted to
find a salvinorin-A induced conditioned place aversion, along with studying changes in
locomotor behaviors in mice. They found that higher doses of salvinorin-A (1.0 mg/kg and 3.2
mg/kg) significantly decreased dopamine levels in the caudate putamen, but not in the nucleus
accumbens. They concluded the inhibitory effects of salvinorin-A on dopamine levels may
contribute to a conditioned place aversion and a decrease in locomotor activity in mice.
In contrast, Braida et al. (2009) studied the effects of salvinorin-A in rodent models of
emotional behavior. They found evidence of anxiolytic and antidepressant effects of salvinorin-A
in rats. Furthermore, their experiments rendered a salvinorin-A-induced increase in dopamine
levels in the nucleus accumbens, which they suggest may be involved in the modulation of affect
and motivation.
Chartoff, Potter, Damez-Werno, Cohen, and Carlezon (2008) investigated the
mechanisms of κ-opioid receptor modulation of striatal function and the potential co-morbidity
to cocaine addiction. One of their findings suggests salvinorin-A was active in the nucleus
accumbens, prefrontal cortex, hippocampus, and central and lateral amygdala. They theorized
that activity in these limbic brain regions may mediate the cognitive effects of salvinorin-A.
Research by Peckys and Landwehrmeyer (1999) states that κ-opioid receptors located in
specific areas of the brain could mediate sedative-like effects. These target areas for sedative
effects of Salvia divinorum include the prefrontal cortex, dorsal and ventral striatal area, lateral
hypothalamus.
Affective Functioning: Introduction to the Affective Process
As previously mentioned, the three areas of exploration (i.e., cognition, affect, and
behavior) are not separate entities. Indeed, cognitive process influences perception and thereby
affective experience. For the purpose of the literature review, the definition of affective
functioning is the process of emotions and feelings that occurs during and after the use of Salvia
divinorum.
Reported affective responses to Salvia divinorum. Common affective responses to Salvia
divinorum have been associated with positive feelings and include euphoria, laughter, calmness,
and improved mood (Baggott et al., 2004; Bucheler et al., 2005; Gonzalez et al., 2006 Siebert,
1994). In the Bucheler et al. (2005) case study, a male teenager reported experiencing an
extracorporal existence in a new “astral body,” which he reported provides a “good” feeling of
recreation. However, not everyone who has used Salvia divinorum reported positive feelings.
Perceptual distortions can lead to feelings of fear and insecurity. People may experience horror,
panic attacks, and anxiety (i.e., “bad trips”). These are believed to be largely due to the loss of
self-control, inability to interact with environment, and disconnection from reality (Bucheler et
al., 2005; Gonzalez et al., 2006). However, in a study by Braida et al. (2009) low doses of
salvinorin-A were found to have a slight anxiolytic effect in rodents. Thus, lower doses of
salvinorin-A may produce an anxiolytic effect while higher doses which produce hallucinations
that may increase anxiety in relation to the psychoactive effects. In addition, dosage and setting
contribute to the type of experience the user encounters, and it is believed that Salvia divinorum
may have only a weak influence on the prevailing mood of the user (Siebert, 1994).
Salvinorin-A and depression. It has been suggested that substances that affect the κopioid receptors can cause alterations in the mood of humans (Pfeiffer, Brantl, Herz, & Emrich,
1986; Roth et al. 2002). Due to the effects of salvinorin-A on human cognition and the influence
of the substance in the limbic areas of the brain, it is believed Salvia divinorum may have a role
in modulation of emotions. Many researchers believe Salvia divinorum may be helpful in
treating mood disorders due to the ability of salvinorin-A to target specific receptors in the brain,
such as k-opioid receptors and not the µ- or δ-opioid receptors or serotonin-2A receptor (5HT2).

A Literature Review on the Status and Effects of Salvia Divinorum on

Transcription

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